The effects of D‐penicillamine (D‐Pen) on the production of immunoglobulins (Ig) and anti‐microbial antibodies (Ab) by human mononuclear cells (MNC) culturedin vitrowere analysed by haemolytic plaque forming cell (PFC) assays. Polyclonal Ig and Ab production, induced by pokeweed mitogen (PWM), was not affected by D‐Pen in pharmacologically relevant concentrations, unless Cu2+, was added. Likewise, D‐Pen + Cu2+, but not D‐Pen alone, affected polyclonal Ig production induced by Epstein‐Barr virus. The production of interleukin‐2 and B cell growth factor by phytohaemagglutinin‐stimulated T cells was not inhibited by D‐Pen; again D‐Pen + Cu2+markedly reduced the production of these cytokines. By contrast, D‐Pen significantly reduced the antigen‐induced antibody production without requirement of additional Cu2+. Addition of cytokine‐containing supernatant to MNC treated with D‐Pen + Cu2+tended to increase the PWM‐induced Ig responses, but had no effect on the antigen‐induced Ab production of MNC cultured with D‐Pen. Thus, the mechanisms by which D‐Pen suppresses polyclonal and antigen‐induc